Mattingly - Cholinergic Pharmacology IV Flashcards
Dantrolene:
MOA
Use
Action
Site of action
MOA: depresses skeletal muscle contraction by blocking release of Ca++ from the SR of skeletal muscles
Use:
o Spasticity type diseases (ie. patients with UMN lesions where reflex activity through the spinal cord below the lesion results in sustained spastic contractions)
o Adjunct during anesthesia to treat malignant hyperthermia
Action: no effect on ACh release, the motor endplate, or the AP conducted down the sarcolemma
Site of action is INTRACELLULAR
Ganglionic Transmission:
Membrane potential changes in post-ganglionic cell bodies contain at least 3 components:
- Rapid, short-duration EPSP (fEPSP)
- Hyperpolarization (IPSP)
- One or more slower EPSPs of low magnitude
What is the first primary event responsible for ganglionic transmission?
Mediated by?
Blocked by? (2)
Rapid, short-duration EPSP (fEPSP): first primary event responsible for ganglionic transmission
Induces depolarization to fire APs in post-ganglionic neuron
Mediated by nAChRs
Blocked by mecamylamine or d-tubocurarine (results in overall block of ganglionic transmission)
What has the primary role to control/prevent excessive neurotransmission through the ganglia
What mechanisms does IPSP use?
Hyperpolarization (IPSP): primary role to control/prevent excessive neurotransmission through the ganglia; due to several mechanisms
Mechanisms:
DA release from accessory cells in ganglion (SIF cells)
ACh stimulation of inhibitory M2 receptors
One or more slower EPSPs of low magnitude are probably mediated by:
One or more slower EPSPs of low magnitude: probably mediated by a combination of M1 receptors and receptors for peptide co-transmitters
Ganglionic Blockade:
Mechanism
Historic use
Ganglionic Blockade:
Mechanism: selective competitive antagonists at nAChRs on the post-ganglionic cell dendrites and cell body within ganglia
- Blocks both SS and PS ganglionic transmission
Historic Use: some of first effective drugs to treat HTN (reduced SS tone to vasculature)
o Tons of unwanted SEs (notably orthostatic hypotension due to inhibition of postural reflexes)
Ganglionic Blockers: (2)
Structure, use, clinical trials (of the second one)
Hexamethonium: classically used in experiments
Mecamylmine:
Structure: secondary amine
Use: rarely used to treat HTN anymore
- Some use in hypertensive emergencies
- Some use in producing controlled hypotension during neurosurgery
Clinical trials: currently being tested for treatment of certain nicotine-sensitive CNS disorders (ie. Tourette’s Syndrome)
CHOLINESTERASE INHIBITION:
MOA and General Effects:
MOA: block access of AChE active site, preventing the breakdown of ACh and magnifying response to physiologically released ACh
IN order for these drugs to be effective cholinergic synapses must be INTACT and FUNCTIONAL
CHOLINESTERASE INHIBITION:
2 classes, examples
Reversible: bind non-covalently to active site of are slowly hydrolyzed by enzyme and therefore only result in temporary inhibition (less than 3 hours)
Physostigmine* Neostigmine* Pyridostigmine Edrophonium Rivastigmine Donepezil Galantamine
Irreversible (Organophosphates): form extremely stable covalent bonds with the esteratic site, resulting in extremely long half-lives (hours to days) and a prolonged duration of action (reversal requires synthesis of new AChE)
Echothiophate*
Malathion (insecticide)
Parathion (insecticide)
Sarin (nerve gas)
Reversible Anticholinesterase Agents:
MOA
Prototypes
MOA: poor substrates for AChE (hydrolyzed slowly) or simple competitive inhibitors of ACh binding
Prototypes:
Physostigmine
Neostigmine
Physostigmine:
Structure
Action
Use
Metabolism
Structure:
natural tertiary amine methyl carbamate
Action:
almost exclusive to AChE at both muscarinic and nicotinic junctions
- Binds covalently at active site of AChE, but is slowly hydrolyzed (reversible)
Use:
- Topical miotic agent in treatment of glaucoma
- Systemic administration for reversal of toxic CNS/peripheral effects of muscarinic blocking agents during OD (atropine, TCAs)
o Not so much anymore due to physostigmine’s potential to cause seizures
Metabolism: ester hydrolysis in the plasma compartment
Neostigmine:
Structure
Action
Binds covalently where:
Stipulation of action:
- Myasthenia gravis?
Structure: synthetic quaternary amine analog of physostigmine
- Therefore, no CNS effects (ie. no seizure potential)
Action:
anticholinesterase activity + some direct agonist action at nAChR
- Binds covalently at active site of AChE, but is slowly hydrolyzed (reversible)
- Stipulation of action only at intact/functional cholinergic synapses may not be entirely true for this drug (can act as direct agonist at synapses not releases ACh)
-Direct agonist action mediated by charged quaternary amine- makes it more effective for management of NM disease like myasthenia gravis
Neostigmine:
Use
Contraindications
Administration
Metabolism
Use:
- Augment motility of GI tract or lower urinary tract
- Reversing skeletal muscle blockade by competitive antagonists
- May also use edrophonium
- Treatment of mysasthenia gravis
o May also use pyridostigmine
Contraindications: cases of mechanical obstruction of GI tract (increased pressure may cause perforation of gut)
Administration: can be given orally but requires much higher doses (1:15 parenteral to enteral ratio)
Metabolism: ester hydrolysis in plasma compartment
Myasthenia Gravis:
General:
Abs bind where?
What improves the strength of contraction in people with this disease?
Congenital form:
Characterized by skeletal muscle weakness that becomes more intense with exercise or as the day progresses
o May progress to point where it is life-threatening
o Auto-immmune disease (Abs bind to nAChRs on motor endplate)
AChE inhibitors improve the strength of contraction in people with this disease
o Congenital form due to various mutations in the nicotinic receptor (~10%)
- Do not benefit from AChE inhibitors
Edrophonium:
Structure Action - Occupies what site? - Potent direct acting agent where: - Where is systemic action? - Duration of action
Structure: synthetic quaternary amine
Action:
Occupies the anionic site of AChE (non-covalent binding) without affecting the esteratic site
Potent direct acting agent at nAChRs on motor endplate
Therefore, systemic action primarily on skeletal muscles with little/no effects at other cholinergic sites (at therapeutic doses)
Duration of action very short (5 minutes)
Edrophonium:
Use
Use:
Diagnostic agent in myasthenia gravis (due to short duration of action)
Patient exercises until muscle weakness present then is given edrophonium
If patient has myasthenia gravis, increase in muscle force will be observed
Not used for chronic treatment of MG because of short duration of action
Pyridostigmine:
Use
Pyridostigmine: very similar to neostigmine, but with longer duration of action
Use:
- Most common oral treatment for MG
- Prophylactic treatment against organophosphate nerve gas
- AChE with pyridostigmine bound will serve as a reserve of free AChE as it is hydrolyzed off AChE after exposure to nerve gas
Weakness During AChE Therapy:
2 causes
How to differentiate between the two:
- Exacerbation of disease or inadequate blood levels of AChE agent: myasthenic weakness
- If given edrophonium, symptoms will improve - Overdose/toxic level of AChE agent: cholinergic crisis (excessive stimulation of motor endplate resulting in depolarizing blockade and muscle weakness)
- If given edrophonium, symptoms will not improve and will intensify
o Distinguishing between the 2: administration of edrophonium (short lived response)
Use of AChE Inhibitors in Alzheimer’s
Disease
Goal
Improves what?
Cholinergic transmission deficiency in the CNS in AD
Goal to maximize ratio of CNS to peripheral inhibition of AChE (to minimize SEs due to cholinergic excess)
May improve cognition in mild-moderate disease, but no evidence for halting dementia progression
AChE Inhibitors used in Alzheimer’s (4)
Tacrine
Donepezil
Rivastigmine
Galamtamine
Tacrine
Use
SEs
Toxicity
AChE Inhibitors used in Alzheimer’s
Tacrine:
Not really used anymore:
Lots of peripheral cholinergic SEs at doses required for cognitive improvement
Hepatotoxic (due to acridine-based structure)
Donepezil:
Structure Action - activity - duration of action - SEs - Hepatotoxicity Metabolism
AChE Inhibitors used in Alzheimer’s
Structure: piperidine-based with tertiary amine
Action: reversible, competitive agent
- Limited activity to improve cognitive function in AD
- Longer duration of action (once daily dosing)
- Milder peripheral cholinergic SEs
- No hepatotoxicity
Metabolism: liver (CYP2D6 and CYP3A4)
- Potential for DDIs (ie. ketoconzaole, quinidine)
Rivastigmine:
Structure
Metabolism
AChE Inhibitors used in Alzheimer’s
Structure: carbamate (binds covalently) with tertiary amine
Metabolism: slowly metabolilzed by cholinesterase (similar to physostigmine and neostigmine, and therefore is reversible)
- Shows little binding to plasma proteins
- Should therefore have less DDIs
Galamtamine:
Structure
Action
AChE Inhibitors used in Alzheimer’s
Structure: tertiary alkaloid (now made synthetically)
Action: reversible and competitive
Memantine:
MOA
AChE-I?
MOA: glutamate receptor antagonist
o Newest drug for AD: may slow deterioration and has limited SEs
Not an AChE-I
Irreversible Anticholinesterase Agents = ?
Organophosphates
Irreversible Anticholinesterase Agents
MOA
- Reactive group:
- Act at:
- Results in:
General MOA:
o All these agents have a reactive phosphate group and some organic substitution
o Act at esteratic site –> phosphorylation of the serine OH group –> very stable covalent bond that is resistant to hydrolysis
o Results in the need for the formation of new enzyme to replace occupied ones
Irreversible Anticholinesterase Agents
General characteristics
What cholinergic transmission sites can be affected?
Very lipid soluble
Can be absorbed through mucous membranes and through intact skin
Widely distributed throughout all tissue compartments
All cholinergic transmission sites can be affected
Echothiophate:
Structure:
Use:
Chronic use associated with:
Only organophosphate employed medically today
Structure: polar and stable in aqueous solution
Use: topical eye administration for sustained miosis (lasts 3 days or longer)
Chronic use associated with high incidence of lens clouding
Malathion vs parathion
Malathion:
Activity: not active until bioactivated in the liver to malaoxon (forms covalent bonds with cholinesterases)
Use:
o Insecticide
o Topical agent for ectoparasites (ie. lice)
o Aerial spraying to control mosquitos
Safer than parathion: can be effectively metabolized in humans (ester bonds can be slowly cleaved)
Parathion:
Activity: same as malathion (bioactivation to paraoxon)
Use: limited to farming and other professional use due to its inability to be detoxified by metabolism in humans
Toxic Effects of AChE Inhibitors:
General
General: toxic effects manifested by CNS, neuromuscular, muscarinic and ganglionic actions
Toxic Effects of AChE Inhibitors:
GI tract motility: BP: HR: Breathing: Micturation: CNS effects NMJ transmission
Increase in GI tract motility (epigastric pain, N/V, involuntary defecation)
Hypotension (marked fall in BP + bradycardia; muscarinin effect)
- Increase in circulating ACh leads to lower peripheral resistance
o Via vascular mAChR (EDRF/NO)
o Via depression of CNS vasomotor center
Reflex tachycardia may be present but peripheral resistance will always remain low
- Death may occur from CV collapse
Difficulty breathing (brochial constriction and increased secretions) -Death may occur via asphyxia
Involuntary micturition
CNS Effects
- Convulsions –> CNS Depression –> Coma
- Death may occur due to decreased/abolished respiration rate due to CNS depression
NMJ Transmission:
- Greatly facilitated at first (muscle fasciculations)
- Eventually results in depolarizing blockade and paralysis
- Death may occur due paralysis of respiratory muscles
Treatment of Organophosphate Poisoning:
Must be started ASAP:
Control muscarinic action with:
Pharmacological antagonist for an excess of ACh at nicotinic site:
What is given to promote regeneration of AChE?
What other supportive measures need to be employed?
Decontamination to prevent further exposure, if necessary
Atropine given in large doses to control muscarinic actions
No pharmacological antagonist for an excess of ACh at nicotinic sites
Pralidoxime given to promote regeneration of AChE
Other supportive measures need to be employed
- Mechanical respiratory support
- Pharmacological BP support
- Benzodiazepines to control convulsions
Pralidoxime Mechanism of AChE Regeneration:
Binds where:
Interaction permits breakage of what?
-Comparison to natural hydrolysis
Why can’t pralidoxime reverse cholinesterase inhibition in the CNS?
Binds anionic site of AChE first, and phosphate moiety of organosphosphate second
Interaction permits breakage of serine-phosphate bond (organophosphate leaves as oxime-phosphate complex)
-Takes place much more rapidly than natural hydrolysis (pralidoxime is a stronger nucleophile than water)
Natural hydrolysis with water leads to an aged adduct that cannot be regenerated with pralidoxime
Since pralidoxime is a quaternary amine, it cannot reverse cholinesterase inhibition in the CNS
